GroupID: 35

DiseaseAssertion: assumed VHL

GroupSize: 10

GroupNumberMales: N/A

GroupNumberFemales: N/A

GroupEthnicity: N/A

GroupAgeRange: N/A

GroupInfo: 10 of the 573 patients discussed in this paper were found to have the following mutation belonging to 2 families altogether.

GroupPresentingHPOs: HP:0006880; HP:0009711; HP:0005584; HP:0002666 (cerebellar hemangioblastoma, retinal capillary hemangioma; renal cell carcinoma; pheochromocytoma)

GroupHPOFreeText: 8 patients had retinal angiomas diagnosed at a mean age of 27Y, 4 had cerebellar hemangioblastomas diagnosed at a mean age of 31Y, 1 member had RCC diagnosed at 50Y, and one has pheochromocytoma diagnosed at 27Y.

GroupNotHPOs: N/A

GroupNotHPOFreeText: N/A

GroupPreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: Supplementary Table S1.

Variant: p.R177* (c.529A>T)

CaseProblemVariantFreeText: N/A

LegacyVariant: N/A

ClinVarID: 625258 https://www.ncbi.nlm.nih.gov/clinvar/variation/625258/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: stop_gained

CivicName: R177* (c.529A>T)

MultipleGeneVariants: N/A

GroupID: 8

Case: 37Y0M, Sex Unknown, Ethnicity Unknown

DiseaseAssertion: assumed VHL

FamilyInfo: 1 of the 573 patients discussed in this paper were found to have this variant. This mutation was found in 1 VHL family with a single patient.

CasePresentingHPOs: HP:0005584; HP:0009711; HP:0006880 (renal cell carcinoma; retinal capillary hemangioma; cerebellar hemangioblastoma)

CaseHPOFreeText: patient had retinal angiomas diagnosed at 28Y, cerebellar hemangioblastomas diagnosed at 22Y, and renal cell carcinoma diagnosed at 37Y.

CaseNotHPOs: HP:0002666 (pheochromocytoma)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: Supplementary Table S1.

Variant: p.R177* (c.529A>T)

CaseProblemVariantFreeText: N/A

LegacyVariant: N/A

ClinVarID: 625258 https://www.ncbi.nlm.nih.gov/clinvar/variation/625258/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: stop_gained

CivicName: R177* (c.529A>T)

MultipleGeneVariants: N/A

PatientID: None

KindredID: 36

Case: Age, sex ethnicity unknown

DiseaseAssertion: unknown; paper focused only on pheochromocytoma

FamilyInfo: No specific family info was present; although this was recorded as a family germline mutation belonging to Family ID 36

CasePresentingHPOs: N/A

CaseHPOFreeText: Unknown

CaseNotHPOs: HP:0002666 (pheochromocytoma)

CaseNotHPOFreeText: No presence of phaeochromocytoma in family

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.R177* (c.529A>T)

CaseProblemVariantFreeText: N/A

LegacyVariant: p.R177* (c.742A>T)

ClinVarID: 625258 https://www.ncbi.nlm.nih.gov/clinvar/variation/625258/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: stop_gained

CivicName: R177* (c.529A>T)

MultipleGeneVariants: N/A

PatientID: N/A

KindredID: Caki-2 (cell line)

Case: Sex Unknown, Age Unknown, Ethnicity Unknown

DiseaseAssertion: Renal cell carcinoma

FamilyInfo: N/A

CasePresentingHPOs: HP:0005584 (renal cell carcinoma)

CaseHPOFreeText: Described as sporadic RCC from cell line Caki-2

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.R177* (c.529A>T)

LegacyVariant: p.R248* (c.742A>T)

CaseProblemVariantFreeText: N/A

ClinVarID: 625258 https://www.ncbi.nlm.nih.gov/clinvar/variation/625258/

CAID: N/A

gnomAD: N/A

VariantEvidence:N/A

MutationType: stop_gained

CivicName: R177* (c.529A>T)

MultipleGeneVariants: N/A

KindredID: 54

GroupID: 49

GroupSize: Unknown

GroupNumberMales: Unknown

GroupNumberFemales: Unknown

GroupEthnicity: Unknown

GroupAgeRange: Unknown

DiseaseAssertion: VHL

GroupInfo: Kindred no. 54 describes a family where at least one member (unspecified how many) had this mutation in the VHL gene. Pheochromocytoma was not observed in this kindred indicating VHL disease type 1.

GroupPresentingHPOs: N/A

GroupHPOFreeText: N/A

GroupNotHPOs: HP:0002666 (Pheochromocytoma)

GroupNotHPOFreeText: Pheochromocytoma was not observed in this kindred indicating VHL disease type 1.

GroupPreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.R177Dfs*25 (c.528del)

LegacyVariant: p.247FS (c.741delG)

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: CA432423454; https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.528del

gnomAD: N/A

VariantEvidence: N/A

MutationType: minus_1_frameshift_variant

CivicName: R177fs (c.528del)

MultipleGeneVariants: N/A

CaseOS-127_II-1: Male, Birth onset, Germany

CasePresentingHPOs: HP:0001992, HP:0410145 (Organic aciduria, Decreased biotinidase activity)

HPOsFreeText: N/A

CaseNotHPOs: HP:0001263 (Global developmental delay)

NotHPOsFreeText: N/A

CaseAddInfo: Parents are non-consanguineous and healthy; Proband is confirmed homozygous via parental testing

CasePreviousTesting: GS-MS analysis identified urinary organic acids dominated by N-aceylated AAs, supported by NMR spectroscopy of urine samples with serum samples being negative; Values of excreted AAs are in Table 1; Biotinidase deficiency treated via 5 mg biotin/d

CaseGenotypingMethod: Genomic DNA was extracted from blood samples or after EBV transformation of peripheral blood lymphocytes. Exons and exon-intron boundaries were amplified and bidirectionally sequenced.

Variant: NM_000666.3(ACY1):c.1057C>T (p.Arg353Cys)

ClinVar: 18110 https://www.ncbi.nlm.nih.gov/clinvar/variation/18110/

gnomAD: 0.004135 (4 homozygotes), https://gnomad.broadinstitute.org/variant/3-52022837-C-T

CaseOS-104_II-1: Male, Birth onset, Turkey

CasePresentingHPOs: HP:0001992, HP:0001324, HP:0002317 (Organic aciduria, Muscular hypotonia, Unsteady gait)

HPOsFreeText: N/A

CaseNotHPOs: HP:0001263, HP:0001252 (Global developmental delay, Muscle weakness)

NotHPOsFreeText: N/A

CaseAddInfo: Parents are consanguineous, Two younger brothers are unaffected, The variant results in a frameshift that extends the WT protein to 408 AAs and affects the C-terminal peptidase domain

CasePreviousTesting: GS-MS analysis identified urinary organic acids dominated by N-aceylated AAs, supported by NMR spectroscopy of urine samples with serum samples being negative; Metabolite pattern of brother was unremarkable; Values of excreted AAs are in Table 1; Ultrasound, electromyography, and NMR tomography of the musculature from the lower extremities showed unremarkable results; Routine histological, histochemical, enzyme histochemical, and immunohistochemical studies did not reveal any significant myopathological abnormalities

CaseGenotypingMethod: Genomic DNA was extracted from blood samples or after EBV transformation of peripheral blood lymphocytes. Exons and exon-intron boundaries were amplified and bidirectionally sequenced.

Variant: NM_000666.3(ACY1):c.1102_1103AC[3] (p.Pro369fs)

ClinVar: 18109, https://www.ncbi.nlm.nih.gov/clinvar/variation/18109/

gnomAD: Not in gnomAD

CaseOS-120_II-1: Female, Birth onset, German/Italian

CasePresentingHPOs: HP:0001992, HP:0011343 (Organic aciduria, Moderate global developmental delay)

HPOsFreeText: N/A

CaseNotHPOs: N/A

NotHPOsFreeText: N/A

CaseAddInfo: Younger brother is unaffected; Proband is confirmed compound heterozygous as mother is heterozygous for R353C but father is unavailable

CasePreviousTesting: GS-MS analysis identified urinary organic acids dominated by N-aceylated AAs, supported by NMR spectroscopy of urine samples with serum samples being negative; Values of excreted AAs are in Table 1; Neuropediatric evaluation performed

CaseGenotypingMethod: Genomic DNA was extracted from blood samples or after EBV transformation of peripheral blood lymphocytes. Exons and exon-intron boundaries were amplified and bidirectionally sequenced.

Variant1: NM_000666.3(ACY1):c.699A>C (p.Glu233Asp)

ClinVar: 18111, https://www.ncbi.nlm.nih.gov/clinvar/variation/18111/

gnomAD: 0.0001846, https://gnomad.broadinstitute.org/variant/3-52021204-A-C

Variant2: NM_000666.3(ACY1):c.1057C>T (p.Arg353Cys)

ClinVar: 18110, https://www.ncbi.nlm.nih.gov/clinvar/variation/18110/

gnomAD: 0.004135 (4 homozygotes), https://gnomad.broadinstitute.org/variant/3-52022837-C-T

CaseOS-124_II-1: Male, Birth onset, Turkey

CasePresentingHPOs: HP:0001992, HP:0001263, HP:0002275, HP:0001252, HP:0002079, HP:0001320, HP:0002188, HP:0003396, (Organic aciduria, Global developmental delay, Poor motor coordination, Muscular hypotonia, Hypoplasia of the corpus callosum, Cerebellar vermis hypoplasia, Delayed CNS myelination, Syringomyelia,

HPOsFreeText: Syringomyelia length of 3.5 cm

CaseNotHPOs:

NotHPOsFreeText:

CaseAddInfo: Parents are consanguineous, Older sister are unaffected, This variant results in a splicing alteration in the acceptor site of Exon 6, skipping exon 6 (amino acid residues 121 to 146) and causing a premature stop codon; Proband is confirmed homozygous via parental testing

CasePreviousTesting: GS-MS analysis identified urinary organic acids dominated by N-aceylated AAs, supported by NMR spectroscopy of urine samples with serum samples being negative; Values of excreted AAs are in Table 1; MRI of the head and spine was performed at age 3 mo

CaseGenotypingMethod: Genomic DNA was extracted from blood samples or after EBV transformation of peripheral blood lymphocytes. Exons and exon-intron boundaries were amplified and bidirectionally sequenced.

Variant: NM_000666.3(ACY1):c.360-1G>A

ClinVar: 18112, https://www.ncbi.nlm.nih.gov/clinvar/variation/18112/

gnomAD: 0.00001767, https://gnomad.broadinstitute.org/variant/3-52020270-G-A

PatientID: 26

KindredID: 31

Case: Sex unknown, Age unknown, French

DiseaseAssertion: VHL

FamilyInfo: None

CasePresentingHPOs: HP:0005584; HP:0030405 (renal cell carcinoma, pancreatic endocrine tumour)

CaseHPOFreeText: N/A

CaseNotHPOs: HP:0002666 (pheochromocytoma)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.R177_L178ins6 (c.531_532ins18)

LegacyVariant: N/A

CaseProblemVariantFreeText: Stated in the paper as: p.R177_L178ins6 (c.531_532ins18) - NM_000551.3:c.531_532ins18: char 24: Syntax error - due to it's non specific nomenclature. (Can't verify coordinates of specific insertion).

ClinVarID: N/A

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: inframe_insertion

CivicName: R177_L178ins6 (c.531_532ins18) 

MultipleGeneVariants: N/A

CaseAM7162: Female, 6 yrs report

CasePresentingHPOs: HP:0001992, HP:0002179, HP:0010864, HP:0008936, HP:0002509, HP:0000750, HP:0011968, HP:0008872, HP:0100247, HP:0002373, HP:0001347, HP:0011449 (Organic aciduria, Opisthotonus, Severe Intellectual disability, Muscular hypotonia of the trunk, Limb hypertonia, Delayed speech and language development, Feeding difficulties, Feeding difficulties in infancy, Recurrent singultus, Febrile seizure, Hyperreflexia, Knee clonus)

HPOsFreeText: Birth weight 2.86 kg, Cranial circumference is 49 cm (3rd percentile), weight 18.6 kg (25th percentile) and height 115 cm (50th percentile) at 6 yrs of age

CaseNotHPOs: N/A

NotHPOsFreeText: N/A

CaseAddInfo: Parents are first cousin consanguineous; Proband is confirmed homozygous for this variant via a QFM‐PCR assay for the dosage of ACY1 exons 12 and 13; Variant leads to skipping of Exon 13 and a resulting frameshift with a premature termination

CasePreviousTesting: Urinary organic acid analysis confirmed by enzyme assay showed elevated levels of N ‐acetylated derivatives of glutamic acid, leucine, valine and isoleucine; Several genetic investigations, such as karyotyping, ring 15 chromosome analysis and mutational analysis of MECP5 and STXBP1 genes, were performed and were found to be normal; MRI showed dilatation of the left temporal horn at the age of 13 months;

CaseGenotypingMethod: Genomic DNA was isolated and the ACY1 gene was PCR-amplified and sequenced. PCR analysis of retrotranscribed RNA was performed to analyze the effect of this variant on splicing.

Variant: NM_000666.3(ACY1):c.1001_1001+5del

ClinVar: 162019, https://www.ncbi.nlm.nih.gov/clinvar/variation/162019/

gnomAD: 0.00001758, https://gnomad.broadinstitute.org/variant/3-52022618-ATGTGAG-A

CaseAC013_II-1: Female, 7 yrs report, Turkey

CasePresentingHPOs: HP:0001992, HP:0001249, HP:0004322, HP:0001513, HP:0030838 (Organic aciduria, Intellectual disability, Short stature, Obesity, Hip pain)

HPOsFreeText: BMI 93rd percentile

CaseNotHPOs: N/A

NotHPOsFreeText: N/A

CaseAddInfo: Parents are consanguineous, Proband is asserted homozygous for this variant

CasePreviousTesting: Identified by the assessment of urinary organic acids by gas chromatography–mass spectrometry; Accumulation of N-acetylated amino acids was much less pronounced than in previously reported patients; Metabolic studies were initiated after the patient complained of pain in her left hip

CaseGenotypingMethod: Genomic DNA was extracted either from peripheral blood or EBV-transformed lymphocytes. PCR-amplification and bidirectional sequencing of all exons and exon-intron boundaries of ACY1 was performed.

Variant: NM_000666.3(ACY1):c.1133G>A (p.Arg378Gln)

ClinVar: 809490, https://www.ncbi.nlm.nih.gov/clinvar/variation/809490/

gnomAD: 0.003104, https://gnomad.broadinstitute.org/variant/3-52022997-G-A

CaseAC007_II-1: Male, 5 yrs onset, Liberia, Black

CasePresentingHPOs: HP:0001992, HP:0002373, HP:0010864, HP:0000729, HP:0000750, HP:0002539, HP:0002282 (Organic aciduria, Febrile seizure, Severe intellectual disability, Autistic behavior, Delayed speech and language development, Cortical dysplasia, Gray matter heterotopia)

HPOsFreeText: N/A

CaseNotHPOs: N/A

NotHPOsFreeText: N/A

CaseAddInfo: Parents are reportedly non-consanguineous, Proband is confirmed homozygous for this variant without parental confirmation via restriction fragment analysis

CasePreviousTesting: Identified by the assessment of urinary organic acids by gas chromatography–mass spectrometry; Accumulation of N-acetylated amino acids was much less pronounced than in previously reported patients

CaseGenotypingMethod: Genomic DNA was extracted either from peripheral blood or EBV-transformed lymphocytes. PCR-amplification and bidirectional sequencing of all exons and exon-intron boundaries of ACY1 was performed. Restriction digest analysis was performed to confirm homozygosity.

Variant: NM_000666.3(ACY1):c.1156C>T (p.Arg386Cys)

ClinVar: 712435, https://www.ncbi.nlm.nih.gov/clinvar/variation/712435/

gnomAD: 0.01775 (3 homozygotes), https://gnomad.broadinstitute.org/variant/3-52023020-C-T

CaseAC014_II-1: Female, 3 yrs report, Lebanon

CasePresentingHPOs: HP:0001992, HP:0025356 (Organic aciduria, Psychomotor retardation)

HPOsFreeText: N/A

CaseNotHPOs: N/A

NotHPOsFreeText: N/A

CaseAddInfo: Parents are consanguineous, Proband is confirmed homozygous for this variant via parental testing, Siblings are healthy

CasePreviousTesting: Identified by the assessment of urinary organic acids by gas chromatography–mass spectrometry; Accumulation of N-acetylated amino acids was much less pronounced than in previously reported patients

CaseGenotypingMethod: Genomic DNA was extracted either from peripheral blood or EBV-transformed lymphocytes. PCR-amplification and bidirectional sequencing of all exons and exon-intron boundaries of ACY1 was performed.

Variant: NM_000666.3(ACY1):c.1132C>T (p.Arg378Trp)

ClinVar: 493363, https://www.ncbi.nlm.nih.gov/clinvar/variation/493363/

gnomAD: 0.00001499 in ExAC, https://gnomad.broadinstitute.org/variant/3-52022996-C-T?dataset=exac

CaseOS-152_II-1: Female, 1 yr report, United Kingdom

CasePresentingHPOs: HP:0001992, HP:0002013, HP:0002013, HP:0040293, HP:0010628, HP:0007359 (Organic aciduria, Vomiting, Bilateral tonic-clonic seizure, Right hemiplegia, Facial palsy, Focal-onset seizure)

HPOsFreeText: N/A

CaseNotHPOs: HP:0001263 (Global developmental delay)

NotHPOsFreeText: N/A

CaseAddInfo: Parents are non-consanguineous, Proband is confirmed compound heterozygous for these variants via parental testing, R353C variant inherited from father but R393H supposedly de novo or mosaic

CasePreviousTesting: Routine urine screening for organic acidurias by gas chromatography–mass spectrometry showed markedly increased urinary excretion of several N-acetylated amino acids; Normal cranial imaging

CaseGenotypingMethod: PCR-amplification and bidirectional sequencing of all exons and exon-intron boundaries was performed on genomic DNA.

Variant1: NM_000666.3(ACY1):c.1057C>T (p.Arg353Cys)

ClinVar: 18110 https://www.ncbi.nlm.nih.gov/clinvar/variation/18110/

gnomAD: 0.004135 (4 homozygotes), https://gnomad.broadinstitute.org/variant/3-52022837-C-T

Variant2: NM_000666.3(ACY1):c.1178G>A (p.Arg393His)

ClinVar: 18114 https://www.ncbi.nlm.nih.gov/clinvar/variation/18114/

gnomAD: 0.006571 (3 homozygotes), https://gnomad.broadinstitute.org/variant/3-52023042-G-A

CaseOS-138_II-1: Female, 4 yrs report, Asian

CasePresentingHPOs: HP:0001992, HP:0002373, HP:0001263 (Organic aciduria, Febrile seizure (within the age range of 3 months to 6 years), Global developmental delay)

HPOsFreeText: N/A

CaseNotHPOs: N/A

NotHPOsFreeText: N/A

CaseAddInfo: Parents are consanguineous, Proband is homozygous for this variant

CasePreviousTesting: Routine urine screening for organic acidurias by gas chromatography–mass spectrometry showed markedly increased urinary excretion of several N-acetylated amino acids

CaseGenotypingMethod: PCR-amplification and bidirectional sequencing of all exons and exon-intron boundaries was performed on genomic DNA.

Variant: NM_000666.3(ACY1):c.589C>T (p.Arg197Trp)

ClinVar: 18113, https://www.ncbi.nlm.nih.gov/clinvar/variation/18113/

gnomAD: 0.00001764, https://gnomad.broadinstitute.org/variant/3-52021009-C-T

CaseOS-146_II-1: Male, 5 yrs report, Romani

CasePresentingHPOs: HP:0001992, HP:0000954, HP:0000431, HP:0000316, HP:0040194, HP:0004322, HP:0001250, HP:0010819, HP:0032792, HP:0002121, HP:0000752, HP:0002342 (Organic aciduria, Single transverse palmar crease, Wide nasal bridge, Hypertelorism, Increased head circumference, Short stature, Seizure, Atonic seizure, Tonic seizure, Generalized non-motor (absence) seizure, Hyperactivity, Moderate Intellectual disability)

HPOsFreeText: N/A

CaseNotHPOs: N/A

NotHPOsFreeText: N/A

CaseAddInfo: Parents are healthy consanguineous cousins, Two cousins and a niece of the mother have epilepsy, Proband is homozygous for this variant

CasePreviousTesting: Routine urine screening for organic acidurias by gas chromatography–mass spectrometry showed markedly increased urinary excretion of several N-acetylated amino acids; Cerebral MRI was normal at the ages of 17 months and 2.5 years

CaseGenotypingMethod: PCR-amplification and bidirectional sequencing of all exons and exon-intron boundaries was performed on genomic DNA.

Variant: NM_000666.3(ACY1):c.1057C>T (p.Arg353Cys)

ClinVar: 18110 https://www.ncbi.nlm.nih.gov/clinvar/variation/18110/

gnomAD: 0.004135 (4 homozygotes), https://gnomad.broadinstitute.org/variant/3-52022837-C-T

CaseVC: Male, Birth onset

CasePresentingHPOs: HP:0030082, HP:0002013, HP:0200048, HP:0001250, HP:0005949, HP:0001290, HP:0001662, HP:0008610, HP:0002120 (Abnormal drinking behavior, Vomiting, Cyanotic episode, Seizure, Apneic episodes in infancy, Generalized hypotonia, Bradycardia, Infantile sensorineural hearing impairment, Cerebral cortical atrophy)

HPOsFreeText: Birth weight of 2565 g, Length of 48 cm, Head circumference of 33 cm, Elevated excretion of TMS-derivatives of N-acetylated amino acids

CaseNotHPOs: HP:0001263 (Global developmental delay)

NotHPOsFreeText: N/A

CaseAddInfo: Parents are non-consanguineous, Proband confirmed homozygous via parental testing

CasePreviousTesting: Cerebral MRI showed abnormal signals in the cortico-subcortical zones of the fronto-parietal and temporo-occipital areas consistent with cortical laminar necrosis; Most presenting phenotypes were ameliorated after 6 weeks of age; N-acetylated amino acid excretion shown in Table 1

CaseGenotypingMethod: RT-PCR confirmed expression of aminoacylase I mRNA was significantly lowered in the proband than in controls. Southern blot and nested PCR confirmed the weak band observed was aminoacylase I mRNA and the relative expression levels. Following this, PCR amplification of all 14 coding exons and flanking introns of ACY1 was performed and sequenced.

Variant: NM_000666.3(ACY1):c.1057C>T (p.Arg353Cys)

ClinVar: 18110 https://www.ncbi.nlm.nih.gov/clinvar/variation/18110/

gnomAD: 0.004135 (4 homozygotes), https://gnomad.broadinstitute.org/variant/3-52022837-C-T

CaseTS: Male, Poland

CasePresentingHPOs: HP:0000256, HP:0001263, HP:0000729, HP:0001992 (Macrocephaly, Global developmental delay, Autistic behavior, Organic aciduria)

HPOsFreeText: Apgar score of 9

CaseNotHPOs: N/A

NotHPOsFreeText: N/A

CaseAddInfo: Parents are non-consanguineous though grandfathers were from neighboring villages, Older brother is healthy, Proband is confirmed homozygous via parental testing

CasePreviousTesting: Biochemical tests included urinary organic acid analysis, amino acid analysis, transaminases, transferrin isoforms, phosphoribosylaminoimidazole-succinocarboxamide (SAICAr), and D-arabinitol; Urinary organic acids analysis by GC-MS was performed repeatedly and revealed N-acetylated derivatives of methionine, glutamic acid, alanine, and glycine in large amounts, as well as leucine, valine, and isoleucine in smaller amounts with brother and parent analysis being unremarkable

CaseGenotypingMethod: PCR amplification and bidirectional sequencing of all exons and exon-intron boundaries was performed on genomic DNA.

Variant: NM_000666.3(ACY1):c.1057C>T (p.Arg353Cys)

ClinVar: 18110 https://www.ncbi.nlm.nih.gov/clinvar/variation/18110/

gnomAD: 0.004135 (4 homozygotes), https://gnomad.broadinstitute.org/variant/3-52022837-C-T